Leber's hereditary optic neuropathy: clinical and molecular genetic results obtained in a family with a new point mutation at nucleotide position 14498 in the ND 6 gene.

Abstract

Mitochondrial DNA mutations at nucleotide position (np) 3460 in the ND 1 gene, np 11778 in the ND 4 gene, and np 14484 in the ND 6 gene are commonly considered to be associated with the clinical features of Leber's hereditary optic neuropathy (LHON) and account for the majority of LHON cases. Recently, a further mutation in the mtDNA at np 14459 was detected. Herein we report the clinical and the most relevant molecular genetic findings obtained in a LHON family with a new mitochondrial DNA mutations at np 14498 in the ND 6 gene. Clinical and historical data were collected over four generations on three affected and five yet unaffected relatives of the maternal line in this family. All three patients and four of their relatives underwent molecular genetic examination. Two patients and five relatives were also studied clinically. All patients exhibited typical clinical features of LHON. In all yet unaffected relatives, various degrees of peripapillary microangiopathy were found. Molecular analysis did not reveal any of the common LHON mutations. Sequence analysis of the mtDNA of one patient was performed and showed a thymine-to-cytosine exchange at np 14498 in the ND 6 gene, leading to the replacement of an evolutionary highly conserved tyrosine by a cysteine residue. The mutation was not found among 70 other LHON lineages and 180 controls. The new mutation at np 14498 lies in the vicinity of the LHON-related mutations at np 14484 and of the recently described mutation at np 14459, in a region constituting the most evolutionarily conserved part of this polypeptide. That the new mutation at np 14498 is found within this highly conserved region and was not present in any controls implies that this mutation is responsible for LHON in this family.